5-substituted-5-(2-thienyl) hydantoins



Patented Jan. 2, 1945 -SUBSTITUTED-5-(2-THIENYL) HYDANTOINS James J. Spurlock, Denton, Tex...

No Drawing. Application March 13, 1942, Serial N 0. 434,585

Claims. This invention relates to 5-substituted-5-(2- thienyl) hydantoins.

Various compositions have been proposed as anticonvulsants for thetreatment of epilepsy and related ailments. Some of these compositions are sedatives and must be used with extreme care, since they seriously restrict the performance of the duties of the patient in the workaday world and in case of sudden discontinuance of the treatment severe seizures or even status epilepticus is quite apt to follow. Consequently the ideal anticonvulsant is one which possesses substantially no sedative properties. Another extremely desirable property of an anticonvulsant is low toxicity; for

the anticonvulsant tobe efiective must be administered daily and a composition with a high toxicity might well result in dire consequences.

In accordance with this invention new compositions are utilized which have marked anticonvulsive activity, which manifest substantially .no hypnotic or sedative efiect, and which possess extremely low toxicity.

The compositions of thisinvention may be represented by the following formula:

in which R represents a hydrocarbon radical,

preferably a hydrocarbon radical having less than 9 carbon atoms, and X represents a member of theclass consisting of hydrogen, the alkali metals, stoichiometric equivalents of alkaline-earth metals, ammonium, the alkylamines, alkanolamines, and polymethylenediamines.

The compositions of this invention are prepared by the following method:

A quantity of a thienyl ketone having the following formula:

m LCD-R S hours at a temperature of between 90? and 150 C. and preferably at 110 C. The mixture isthen cooled, and about 1% molecular equivalents of an alkali cyanide and about 1 molecular equivalent of ammonium carbonate are. added. The

mixture is then heated under pressure at approximately C. for an additional fi, to 24 hours. The mixture is removed from the pressure apparatus and about half of the liquid evaporated. The mixture separates into two layers, an oily and a water-soluble layer, in which any unreacted ketone is contained in the oily layer. The mixture is acidified with a mineral acid, such as concentrated hydrochloric acid, and extracted twice with portions of an organic solvent, such as ether or benzene. The combined organic solvent extract is agitate with at least two portions of a dilute water solution of an alkali hydroxide and the alkali hydroxide solution is then acidified with a mineral acid, such ashydrochloric acid, and heated to expeltheorganic solvent. The 5-R-5- (2thienyl)hydantoin separates and is purified by any suitable means, such as recrystallization.

Desirably, R. does not contain more than 9 carbon atoms. It may be, for example, the methyl, ethyl, n-butyl, iso-butyl, n-amyl, isoamyl, 2-ethylbutyl, secondary amyl, n-hexyl, phenyl, benzyl,

phenylethyhtolyl, xylyl, cyclobutyl, cyclopentyl,

,or cyclohexyl groups. Preferably, the sodium salt of the 5-R-5-(2-thienyl) hydantoin is used although other salts, such as the potassium, am-

monium, lithium, calcium, magnesium, stronti um, ethanolamine, and ethylenediamine salts may also be used. e

,The salts of the 5-R- 5-(2-thienyl)hydantoin are prepared by reactingstoichiometric proportions of the 5-R-5-(Z-thienyDhydantOin and an alkoxide of the required metal, ammonium or substituted ammonium. For example, the sodisalt is preparedby reacting equal molecular proportions of sodium ethoxide and the 5-R-5-(2- 5-R-5 -(2-thienyl) hydantoin dissolved in a suitable solvent, such as ethanol, is reacted with an equal molecular quantity of the substituted ammonium base, such as ethanolamine or ethylenediamine. The reaction is substantially immediate. To obtain the dry salt, the solution in any case is evaporated and the evaporation completed 'under vacuum.

Typical examples of the compositions of this invention are as follows:

Example 1-Preparation 5-melM Z-5-(2-thie-- nyZ) hydantoin Three and seventy-nine hundredths grams (0.03 mol) of methyl- (Z-thienyl) ketone dissolved in 75 cc. of ethanol is added to a solution of 3.25 g. (0.045 mol) of 90 percent potassium cyanide and 10.2 g. (0.09 mol) of ammonium carbonate in 75 cc. of water. The solution is placed in a small autoclave and heated for 19 hours at a 178.3-179 C. (corrected). Analysis reveals 12.28 percent nitrogen compared with a theoretical value of 12.49 percent nitrogen.

Example 4-Preparation 0 5-n-butyl-5-(2-thie- 'nyl) hydantoin This preparation is conducted in a manner similar to that described in Example 1. The following proportions are used: n-butyl-(Z-thienyl) ketone, 5.05 g. (0.03 mol); potassium cyanide, 3.25 g. (0.045 mol) ammonium carbonate, 10.2 g.

(0.09 mol) in 100 cc. of 50 percent ethanol. The

temperature of about 110 C. There is then added 3.25 g. of potassium cyanide and 3 g. of ammonium carbonate. Heating is continued in the autoclave for an additional 18 hours at the same temperature. During these heatings of the reaction mixture, the 5-methyl-5-(2-thienyl)hydane toin is formed. The reaction mixtureis removed and about half of the liquid evaporated, an oil .salt thereof, is acidified with hydrochloric acid and heated to expel ether. An oil, which is the 5-.methyl-5-(2-thienyl)hydanto-in, separates and on cooling solidifies, The yield of the 5-methyl- 5-(2-thienyl) hydantoin is approximately 62 percent of the theoretical. After several recrystaltime of the first heating is 18 hours at 110 C.

' Three and twenty-five hundredths grams of polizations from dilute alcohol the compound melts at .138.5"140 C. (corrected). Analysis reveals 14.49 percent nitrogen compared with a theoretical value of 14.32 percent nitrogen.

' EacampZe 2--P-repa.mtion of 5-ethyl-5-(2-thienyl) hydantoz'n Four and twenty-five hundredths grams. (0.03

mol) of ethyl-(Z-thienyl) ketone, 2.8 g. (0.039. mol) of potassium cyanide, and 11.0'g. (0.097 x mol) of ammonium carbonate in 100 cc. of

.percent ethanolare placedin an autoclave in accordance withjthe procedure outlined in .Ex-

ample 1 and heated for21 hours at about 110 C.

The reaction .mixturejis evaporated to one half of its original volume, acidified, extracted with ether and the ether solution extracted with potassium hydroxide solution as outlined in Example 1. The yield of the crude compound, which with a theoretical value of 13.33 percent nitrogen. Example 3-Preparation of 5-n-propy'l-5- (Z-thienyl) hydantoin A mixture of 4.6 g. 0.03 1101) of n-propyl-(Z- thienyl) ketone, 3.25 g. (0.045 mol) of potassium cyanide, and 10.2 g. (0.09 mol) of ammonium carbonate in 150 cc. of 150 percent ethanolis heated in an autoclave for10 hoursat a temperature of C. There'is then added 2.17 g. (0.03 mol) of potassium cyanide and 3 g. of ammonium carbonate and the mixture is heated in an autoclave for 20 hours at 95 C. The B-n-propyl-B- (Z-thienyDhydantoin is purified as describedin Example 1. The yield of the crude 5-n-propyl-5- (Z-thienyllhydantoin is about 86 percent and the melting point of 'the purified product is abQ lt (corrected) tassium cyanide and 3 g. of ammonium carbonate are added and the heating continued for an additional 18 hours at 110 C. The yield of crude "5-n-1butyl-5-(Z-thienyl)hydantoin is about as percent and the melting point of the purified material is 230-231 C. (corrected). Analysis reveals 11.91 percent nitrogen compared with a theoretical value of 11.76 percent nitrogen.

Example 5-Preparation of 5.-namyl-5.-(2-thienyl) hydantoz'n The preparation of 5-n-amyl-5-(2-thienyl)hydantoin is conducted in a manner similar to that described in Example 1. The following proportions are used: n-amyl-(Z-thienyl) ketone, 5.46

g. (0.0311101); potassium cyanide, 3.25 g. (0.45

mol); ammonium carbonate, 10.2 g. (0.09 mol) in cc. of .50 percent ethanol. The initial period of heating is 24 hours at C. Three and twenty-five hundredths grams of potassium cy anide and 3 g. of ammonium carbonate are added and the mixture heated for 22 hours at 110 C. The yield of crude 5-n-amyl5- (Z-thienyl) hydantoin obtained is about 82 percent and the melting point of the purified material is 154-154.7 C. (corrected). Analysi reveals 10.97 percent nitrogen compared with a theoretical value of 11.11 percent nitrogen.

Example 6-.-Preparati0n of 5-phenyle5-(2-thienyl) hydantoin The 5-phenyl-5-(Z-thienyllhydantoin is prepared by heating a mixture of 5 .64 g. (0.03 mol) of phenyl-(Z-thie'nyl) ketone, 3.25 g. (0.03 mol) of potassium cyanide and 10.2 g. (0.09 mol) of ammonium carbonate in 75 cc. of 50 percent" ethanol for 28 hours at a temperature of about 110C. An additional 3.25 g.,of potassium cyanide and 3 g. of ammonium carbonate, are added and the mixture heated for 24 noursat about 110 C. .By the process of purification described in Example 1, 4.3 g. of 5-,phenyl-5 -(2-thienyl)hy dantoin is obtained, and from -,the ether layer, 2.2 g. of unreacted ketone. The yield of :the

5-.phenyl-5- (2-thienyl). hydantoinis about 56.,per-

cent. The melting point ofthepurified 5-phenyl- 5-.(2-thienyDhydantoin is about 2. .913 C.

The 5-(l-ethylpropyl) -5-' ('2-thieny1) hydantoin isprepared in the same manner as'the5-methyl- 5-(2-thienyl)hydantoin described inExampl'e 1 ce t a he ol ne tcr al n'dquantlt e r m l y d; et y o y .-(Z-t Yl) ket e. -4 (.03 mo potass um cy ide. .25%- .(0-45 mol); mmon m car Qnate..- 0-2 a 1 .1 1) in 1.0 c o pe cen ethanet 1 hexy1-5- (2-thienyl) hydantoin and temperature of heating is the same as that described in Example 1. After the reaction mixture has been heated for 19 hours at 110 (3., as described in Example 1,there is added 3.25f'g. of potassium cyanide and 3 g. t ammonium carbonate andtheheatingds continued inan autoclave foran additional 18 hours. During these heatings of the reaction mixture the 5-(1-ethylpropyl)-5-(2-thienyl)hydantoin is formed. The yield of the crude 5-(1-ethylpropyl)-5-(2-thienyl) hydantoin is about 13 per cent of the theoretical andthe melting point of the purified material is about 208-208.5 .C. (corrected).

Erainple 8-Preparation of 5-is0butyl-5- (2- thienyuhydantoin i l The 5-isobutyl-5- (Z-thienyl) hydantoin is prepared in the same manner as the 5-methyl-5-(2- thienyllhydantoin described in Example 1 except that 5.04 g. of isobutyl-(Z-thienyl) ketone is used instead of the methyl-'(z-thienyl) ketone employed in Example 1. Theyield of the crude 5-isobutyl-5-(Z-thienyl)hydantoin is. about 71 percent of the theoretical and the melting point of the purified product is about 155-15 6.5 C.

icorrected). i

Example y-prepamtion of 5 -cycZohex11Z 5-Y2- thienyllhydantoin Three and twenty-five hundredths grams of potassium cyanide is dissolved in 250 cc. of propylene glycol. To the solution is added 10.2 g. of ammonium carbonate and. 5.82 g. of cyclohexyl- (Z-thienyl) ketone in an autoclave. The material is heated for 18 hours at 110 C. An additional 3.25 g. of potassium cyanide and 3 g.;of ammonium carbonate are thenadded'andythe heating continued for an additional 18.hours at 110 C. The cooled reaction mixture is diluted with 5 volumes of Water and acidified with concentrated hydrochloric acid. 1 The crude 5-cyclois recrystallized from alcohol. The yield of the crude 5-cyclohexyl-5-(2-thienyl) hydantoin is about '71 percent and the purified 5-cyclohexyl-5-(z-thienyl) hydantoin melts at about 244 245 C. rected).

Erample 10-Preparation of 5-(,6 phenylethyl)- 5- (Z-thienyl) hydantoin The. S-(B-phenylethyl) 5-. (2-thienyl) hydantoin is prepared in the same manner as the 5-methyl- 5-(2-thienyl)hydantoin described in Example 1 except that-6.48 g. of'p-phenylethyl-(Z-thienyl) ketone is employed instead of the methyl-(2- thienyl) ketone employed in Example 1. The yield of the crude b-(fi-phenylethyl) -5-(2-thienyl) hydantoin is about 52 percent of the theoretical and the melting point of the purified 5-(p-phenylethyl) -5-( -thieny1)hydantoin is about l83-184 C. (corrected).

Example 11Preparation of 5-o-tolyl-5-(2 -thienyl) hydantoin The 5-o-tolyl-5-(2-thienyl)hydantoin is prepared in a manner similar to that described in Example 9for the preparation of 5-cyclohexyl- 5-(2-thienyl)hydantoin except that 6.06 g. of

, o-tolyl-(Z-thienyl) ketone is used instead of the cyclohexyl-(Z-thienyl) ketone employed in Example 9 and 200 g; of acetamide is used instead of the propylene glycol employed in Example 9.

(corr ed to dryness in vacuo,

of traces of alcohol the residue is. heated under Example 12-Preparatz'on of the sodium salt of 5 -phenyl-5- (Z-thienyl) hydantoin To a solution of 11.33 g. of 5-phenyl-5-(2-thienyDhydantoin in 250 cc. of absolute ethanol is added a solution of sodium ethoxide prepared by adding 1.01 g. of sodiumto cc. of absolute ethanol. The reaction mixture is then evaporated to dryness in vacuo. To insure the removal of traces of alcohol the residue is heated under vacuum on a steam bath. The residue is the sodium salt of 5-phenyl-5-(2-thienyl)hydantoin, Other alkali metal salts, such as the potassium and lithium salts of 5-phenyl-5-(2-thienyD- hydantoin are prepared in a similar manner except that potassium ethoxide or lithium ethoxide is employed instead of the sodium ethoxide.

Example Iii-Preparation of the calc um salt of 5-isobutyl- 5- (Z-thienyl) hydantoin To a solution of 3.57 g. of 5-isobutyl-5-(2 -thienyDhydantoin in 100 cc. of absolute ethanol is added a solutionjof calcium ethoxide prepared by dissolving. 1.2 g. of calcium in 100 cc. of absolute ethanol. The'reactionmixture is then evaporatvacuum on a steam bath. The residue is the calcium salt of 5-l-isobutyl-5-(2-thienyl)hydantoin. Other alkaline-earth metal salts, such as the barium, strontium, and magnesium salts of 5-isobutyl-5-(Z-thienyDhydantoin are prepared in a similar manner exceptthat barium, strontium, or magnesium alkoxidesare employed instead of calcium ethoxide;

Example 14-1 reparation of ethano lamine salt of 5 -n-amiyZ -5- (Z-thzenyl) hydantoin To a solution of 7.56 g. of 5-n-amyl-5-(2- thienyDhydantoin in 100 cc. of absolute ethanol is addeda solution of 1.83g. of ethanolaminein 10 cc. of absolute ethanol. The reaction mixture is then evaporated to dryness in vacuo.. To in sure theremoval of traces of alcohol, the residue is heated under vacuum on a steam bath. The

residue is the ethanolamine salt of 5-n-amyl-5- (2-thienyl) hydantoin. Other alkanolamine salts, such as the propanolamine salt of 5-n-amyl-5 (2-thienyl)hydantoin are'prepared in a similar manner except that the appropriate alkanolamine is employed instead of ethanolamine.

Example 15-Preparation of the mono-5-cyclohexyl-S-(Z-thienyl) hydantoin; salt of ethylenediamine To a solution of 5.28 g.. of5-cyclohexyl-5- (Z-thienyDhydantoin in 150 cc. of absolute ethanol is added a'solution of 1.2 g. of ethylenediamine in 25 cc. of absolute ethanol. The reaction mixture is then evaporated to dryness in vacuo. To insure the removal of traces of alcohol, the residue is heated under vacuum. on a steam bath. The residue is the mono-5-cyclohexyl-5-(2-thienyl)hydantoin salt of ethylenediamine.

If the di-5-cyclohexyl-5-(Z-thienyl)hydantoin salt of ethylenediamine is desired, 0.6 g. ot'eth 'ylenediamine isreacted with the solution containing 5.28 g. of the 5-cyclohexyl-5- (Z-thienyD- hydantoin.

Other alkylenediamine salts of the 5-cyclohexyl-5-(2-thienyllhydantoin may be prepared in similar manner by employing. equivalent quantities of the required alkylenediamines instead of the ethylenediamine.

To insure the removal -What is; claimed is: 1. A 5 substituted-5 -'2- th ien-yl).-hydantin which is represented by the following formula:

po m-x s, l-\ a R NH- 0 in which R represents a hydrocarbon radical, and X represents a member of'the class, consisting of hydrogen, the alkali metals, stoichiometric equivalentsof alkaline-earth-metals, ammonium, alkylamines, allcano-lamines, and polymethylene diamines. V I, v 2. A 5- substituted- 5 -(2 thienybhydantoin which. is representedby the following formula;

R NH 0 in which, R represents a saturated alkyl radical having less than 9 carbon atoms and X represents a member of the class consisting of hydrogen, the alkali metals, stoichiometricequivalents of alkaline-earth metals, ammonium, alkylamines, alkanolamines, and polymethylene diamines.

3. A 5 -substituted- 5 -(2 -thienyl')hydantoin which is represented by 'thefollowing formula:

' ooN--x S p O in which R represents a saturated branch chain alkyl radical having-less than 9 carbon atoms and X represents a member of the class consisting of hydrogen, the alkali metals, stoichiometric equivalents of alkaline-earth fmetals, ammonium,

alkylamines, alkanolamines, and polymethylene diamines.

4. A 5 substituted 5 -(2 thienyl) hydantoin which is represented by the following formula:

in which R is a hydrocarbon radical.

5. A 5 substituted 5 -(2 thienyl) hydantcin which is represented by the following formula:

- R NH- 0 V in which R is an acyclic hydrocarbon radical and which is represented by the following formula:

CO N--Na ll ll \S/ I R NH-COR in which R. is a straight chain alkyl group having less than 9 carbon atoms.

8. A 5 substituted 5 2 thienyl) hydantoin which is-represented by the following formula:

T l s R NH- ,0

in which R is a branch chain alkyl group having less than 9 carboniatoms.

9. -A 5 phenyl-5(2-thienyl)hydantoin which is represented by the following formula:

in which X represents a member of the class consisting of hydrogen, the alkali metals, stoichiometric equivalents of alkaline-earth metals, ammonium, polymethylene diaminesQ V 10. The sodium salt of 5-methy1-5(2-thienyll)- hydrantoin.

JAMES 'J. SPURLOCK.

alkylamines, alkanolamines, and I 

